Summary Ricin is a potent toxin whose wide availability and ease of purification has resulted in its development as an agent of bioterrorism. The most likely and lethal means of delivery of ricin by terrorists to human populations would be by aerosolization. The consequences of aerosol delivery of ricin occur predominantly in the lungs, which develop acute injury and an inflammatory pathology, characterized by edema, influx of neutrophils, and apoptosis. Ricin's toxicity stems from the depurination of a single adenine with the "sarcin/ricin" loop of 28S ribosomal RNA. This event results not only in the inhibition of protein translation, but also in the intense and extended activation of the stress-activated protein kinases, JNK and p38 MAPK. These kinases are central mediators of inflammatory responses that are responsible for inducing the transcription of proinflammatory cytokines and chemokines. Published studies by us and others have identified macrophages as a target for ricin, inasmuch as alveolar macrophages undergo apoptosis in response to ricin and release their mediators into the pulmonary environment prior to the death of these cells. Additionally, we determined that mice deficient in expression of interleukin-1 (IL-1) or its receptor, IL-1R1, likewise fail to develop inflammatory pathology in response to aerosolized ricin. Preliminary studies show that one mechanism of ricin's actions is to stimulate transcription of inflammatory genes through the ZAK, a MAP3K. A second action of ricin (and other inhibitors of protein synthesis) is to induce the processing and secretion of IL-1beta by promoting activation of the NALP3 inflammasome. We outline a research plan that has two major goals: 1) to determine the mechanisms by which signals generated by ricin result in pulmonary inflammation and mortality;and 2) to identify and administer potential agents that can be administered therapeutically to suppress the toxic effects of ricin. The first aim will be to employ proteomics to identify the components of the ricin-activated inflammasome. The second aim will define the participation of reactive oxygen species in ricin-mediated activation of inflammasomes. The third aim will be to elucidate the role of caspase-1-induced death of macrophages in promoting pulmonary inflammatory responses induced by ricin. The fourth aim proposes to intervene therapeutically in ricin-mediated inflammation in mice by administering: a) IL1Ra/Anakinara, an IL-1 receptor inhibitor;and b) small molecular inhibitors of ZAK kinase, a mediator of ricin's proinflammatory activities. These studies would be significant not only for intervening in the actions of ricin, but also for suppressing the proinflammatory actions of other inhaled compounds.